5 Significant Developments With CAR-T Therapy

Novartis has won the race to being the first company to have its chimeric antigen receptor-T (CAR-T) gene therapy treatment approved by the FDA. This much-awaited approval is expected to change the paradigm for treating pediatric and young adults diagnosed with B-cell precursor acute lymphoblastic leukemia (ALL).

Here’s a look at some of the major developments in the CAR-T space:

1. Trials in solid tumors

CAR-T cells have primarily been developed for treating patients with hematological disease; however, a report published earlier this year presented a case study of the effectiveness of this leukapheresis-based treatment in glioblastoma (GBM). The single-patient study treated a 50-year-old man with multiple lesions that were nonresponsive to other lines of therapy and were progressing. At a 7.5-month follow-up after the last infusion of modified CAR-T cells, existing tumors were undetectable by positron emission tomography and could not be measured by magnetic resonance imaging. However, new tumors had developed.

2. Biomarkers of response

At the 2016 annual meeting of the American Society of Hematology, Jan Joseph Melenhorst, PhD, from the Perelman School of Medicine at the University of Pennsylvania, presented results from a study evaluating biomarkers of response to anti-CD19 CAR T-cell treatment in patients diagnosed with chronic lymphocytic leukemia. Patients with persistent functional T cells had the most durable response.

Transcriptomic signatures of the T cells showed that T cells from nonresponders expressed genes that regulate terminal differentiation and exhaustion. Responders had early memory T cells, which may mediate superior antitumor activity due to enhanced proliferation and survival following adoptive transfer.

3. ODAC nod for Novartis treatment

In mid-July, the FDA’s Oncologic Drugs Advisory Committee, commonly referred to as ODAC, unanimously approved tisagenlecleucel or CTL019 for the treatment of children and young adults with relapsed or refractory B-cell ALL. The commercialization of this treatment was the result of a partnership between Novartis and the University of Pennsylvania.

Cytokine-release syndrome (CRS) is a significant side effect of this treatment. David L. Porter, MD, one of the pioneers of CAR-T research, told The American Journal of Managed Care^® (AJMC^®) that using a monoclonal antibody to block interleukin-6, which is a major cytokine responsible for CRS, can rapidly reverse the associated complications including high fevers, myalgias, arthralgias, and muscle and joint aches. Novartis has developed a Risk Evaluation and Mitigation Strategy to effectively communicate the symptoms and treatment to care providers.

4. Tisagenlecleucel (Kymriah) approved by the FDA

This week, the FDA approved tisagenlecleucel. Marking this historic moment was a statement from the new FDA commissioner, Scott Gottlieb, MD: “We’re entering a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer,” he said. “New technologies such as gene and cell therapies hold out the potential to transform medicine and create an inflection point in our ability to treat and even cure many intractable illnesses.”

The FDA also approved tocilzumab (Actemra) for the treatment of CAR T cell-induced severe or life-threatening CRS in patients 2 and older.

5. The big question is affordability

The treatment is expensive: $475,000. Although only a small number of patients would qualify for the current indication of tisagenlecleucel, several ongoing trials, as well as similar treatments being developed by Kite Pharma (recently bought by Gilead Sciences) and Juno Therapeutics, will soon expand the indications for CAR T-based treatments.

With this in mind, CMS is working with stakeholders to develop innovative payment agreements such as outcome-based pricing. In a statement released following the announcement of tisagenlecleucel’s approval, CMS Administrator Seema Verma said, “Innovations like this reinforce our belief that current healthcare payment systems need to be modernized in order to ensure access to new high-cost therapies, including therapies that have the potential to cure the sickest patients. Improving payment arrangements is a critical step towards fulfilling President Trump’s promise to lower the cost of drugs.”

“I think it’s the beginning of a fascinating era in immuno-oncology,” Bruce Feinberg, DO, vice president and chief medical officer, Cardinal Health Specialty Solutions, told AJMC^® in an e-mail. “Kite’s CAR-T is likely to follow in 6-12 months and Juno thereafter. Bluebird’s product for myeloma is next in queue and shelf-stable products from folks like Cellectis move the paradigm to the next level. All of this may well happen in the next 3 to 5 years.”

Feinberg feels that the current wave of CAR-T therapies will have the biggest impact on relapsed and refractory hematologic malignancies, “this is a finite population for which the early-to-market companies will be competing. If the technology succeeds in primary refractory solid tumors like GBM, then it's Katie bar the door, with respect to societal cost.” He added, however, that early CAR-T indications will most likely compete with allogenic hematopoietic stem cell transplant (HSCT) and that “the initial Novartis price is not a far cry from aggregated allogenic HSCT cost. Therefore, I don’t believe this initial price will be a significant factor in treatment adoption.”